Background: Nivolumab plus chemotherapy is a standard first-line treatment for advanced gastric cancer (GC), but reliable early biomarkers for predicting treatment outcomes remain lacking. This study aimed to identify early immunological predictors through dynamic immune profiling.Methods: Fifty patients with advanced or unresectable GC receiving nivolumab plus XELOX or FOLFOX were enrolled. Peripheral blood was collected at baseline, week 1, and week 6. Plasma biomarkers (Granzyme B, Ki-67, CXCL10, IFN-γ, TGF-β1) were measured by ELISA, and immune cell subsets, including cytotoxic T cells, immune checkpoint–positive populations, and memory T-cell subsets, were analyzed by flow cytometry. Cutoffs were defined by medians, established thresholds for NLR and lymphocyte count, and criteria for long-term response (≥9.5 months). Associations with response and progression-free survival (PFS) were evaluated using Kaplan–Meier analysis, Cox regression, and ROC curves.Results: Early responders exhibited significant increases in Granzyme B and CXCL10, with ΔGranzyme B alone and in combination with ΔKi-67 predicting response with high accuracy. A lower week 1 neutrophil-to-lymphocyte ratio was associated with long-term benefit. Elevated week 1 CD8+T-cell proportion and greater decreases in PD1+CD69+Ki-67+CD8+T cells were linked to improved PFS. Higher baseline PD1+LAG-3+Ki-67+CD8+T-cell levels and combined TIM-3+/LAG-3+expression enhanced prognostic stratification. Additionally, elevated baseline activated TEMRA cells and declines at week 6 in the same subset correlated with better outcomes.Conclusions: These findings highlight the clinical utility of serial immune monitoring to enable early treatment stratification and guide personalized immunotherapy strategies in advanced GC.
背景：纳武利尤单抗联合化疗是晚期胃癌（GC）的标准一线治疗方案，但尚缺乏可靠的早期生物标志物来预测治疗结果。本研究旨在通过动态免疫分析识别早期免疫学预测因子。 方法：研究纳入50例接受纳武利尤单抗联合XELOX或FOLFOX治疗的晚期或不可切除GC患者。分别于基线、第1周和第6周采集外周血样本。采用ELISA法检测血浆生物标志物（颗粒酶B、Ki-67、CXCL10、IFN-γ、TGF-β1），并通过流式细胞术分析免疫细胞亚群，包括细胞毒性T细胞、免疫检查点阳性群体及记忆T细胞亚群。截断值依据中位数、已确立的中性粒细胞-淋巴细胞比值（NLR）与淋巴细胞计数阈值以及长期缓解（≥9.5个月）标准确定。采用Kaplan-Meier分析、Cox回归和ROC曲线评估指标与治疗反应及无进展生存期（PFS）的关联。 结果：早期应答者表现出颗粒酶B和CXCL10的显著升高，其中Δ颗粒酶B单独或联合ΔKi-67可高精度预测治疗反应。第1周较低的中性粒细胞-淋巴细胞比值与长期临床获益相关。第1周CD8⁺ T细胞比例升高及PD1⁺CD69⁺Ki-67⁺CD8⁺ T细胞更大程度的下降与改善的PFS相关。基线期较高水平的PD1⁺LAG-3⁺Ki-67⁺CD8⁺ T细胞及TIM-3⁺/LAG-3⁺联合表达可增强预后分层能力。此外，基线期活化的终末分化效应记忆T细胞（TEMRA）水平升高及该亚群在第6周的下降与更好的临床结局相关。 结论：这些发现凸显了连续免疫监测在晚期胃癌早期治疗分层和指导个体化免疫治疗策略中的临床价值。
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